Accelerated Fentanyl Metabolism During Pregnancy and Impact on Prenatal Drug Testing.

OBJECTIVE: To evaluate the metabolic pattern of illicit fentanyl in a sample of pregnant patients with opioid use disorder. Fentanyl pharmacokinetics during pregnancy are currently understudied yet the interpretation of a fentanyl immunoassay during pregnancy has significant implications on maternal legal custody and child welfare. Through this medical-legal lens, we demonstrate the utility of an emerging metric, the metabolic ratio, for accurate analysis of fentanyl pharmacokinetics during pregnancy. METHODS: We conducted a retrospective cohort analysis using the electronic medical records of 420 patients receiving integrated prenatal and opioid use disorder care at a large urban safety net hospital. Data related to maternal health and substance use were collected for each subject. The metabolic ratio was calculated for each subject to measure their rate of metabolism. The sample's (n = 112) metabolic ratios were compared with a large non-pregnant sample (n = 4366). RESULTS: The metabolic ratios of our pregnant sample were significantly (p = .0001) higher than the metabolic ratios of our non-pregnant sample, indicating that the rate of conversion to the major metabolite was faster in pregnant people. The effect size for this difference between the pregnant and non-pregnant sample was large (d = 0.86). CONCLUSIONS FOR PRACTICE: Our findings characterize the unique metabolic pattern of fentanyl in pregnant people who use opioids, providing guidance for institutional policies around fentanyl drug testing. Additionally, our study warns of misinterpretation of toxicology results and stresses the importance of physician advocacy on behalf of pregnant women who use illicit opioids.

What is already known on the subject? Widespread use of illicit fentanyl is a dangerous public health threat yet little is known about fentanyl metabolism.What this study adds? This study highlights the difference between fentanyl metabolism in pregnant and non-pregnant people. Providers caring for pregnant patients must be cautious when interpreting fentanyl test results since a positive test may not always indicate recent use. These data can assist in accurate interpretation of urine fentanyl tests during pregnancy.

In Situ Electrochemical Monitoring of Caged Compound Photochemistry: An Internal Actinometer for Substrate Release.

Caged compounds are molecules that release a protective substrate to free a biologically active substrate upon treatment with light of sufficient energy and duration. A notable limitation of this approach is difficulty in determining the degree of photoactivation in tissues or opaque solutions because light reaching the desired location is obstructed. Here, we have addressed this issue by developing an in situ electrochemical method in which the amount of caged molecule photorelease is determined by fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes. Using p-hydroxyphenyl glutamate (pHP-Glu) as our model system, we generated a linear calibration curve for oxidation of 4-hydroxyphenylacetic acid (4HPAA), the group from which the glutamate molecule leaves, up to a concentration of 1000 µM. Moreover, we are able to correct for the presence of residual pHP-Glu in solution as well as the light artifact that is produced. A corrected calibration curve was constructed by photoactivation of pHP-Glu in a 3 µL photoreaction vessel and subsequent analysis by high-performance liquid chromatography. This approach has yielded a linear relationship between 4HPAA concentration and oxidation current, allowing the determination of released glutamate independent of the amount of light reaching the chromophore. Moreover, we have successfully validated the newly developed method by in situ measurement in a whole, intact zebrafish brain. This work demonstrates for the first time the in situ electrochemical monitoring of caged compound photochemistry in brain tissue with FSCV, thus facilitating analyses of neuronal function.

Competing pathways for photoremovable protecting groups: the effects of solvent, oxygen and encapsulation.

Extending the applications of Photoremovable Protecting Groups (PPGs) to "cage" phenols has generally met with unusually complex PPG byproducts. In this study, we demonstrate that the p-hydroxyphenacyl (pHP) cage for both simple and complex phenolics, including tyrosine, dispenses free phenols. With the simpler unsubstituted phenols, the reaction is governed by their Brønsted Leaving Group ability. On the other hand, the byproducts of the cage vary with these phenols. For the more acidic phenols the cage byproduct follows the Favorskii rearrangement to form p-hydroxyphenylacetic acid whereas for the weaker phenols other reactions such as reduction and hydrolysis begin to emerge. When the photolysis is conducted in octa acid (OA) containers, non-Favorskii, unrearranged fragments of the cage and other byproducts arise.

Negative Ions in Space.

Until a decade ago, the only anion observed to play a prominent role in astrophysics was H-. The bound-free transitions in H- dominate the visible opacity in stars with photospheric temperatures less than 7000 K, including the Sun. The H- anion is also believed to have been critical to the formation of molecular hydrogen in the very early evolution of the Universe. Once H2 formed, about 500 000 years after the Big Bang, the expanding gas was able to lose internal gravitational energy and collapse to form stellar objects and "protogalaxies", allowing the creation of heavier elements such as C, N, and O through nucleosynthesis. Although astronomers had considered some processes through which anions might form in interstellar clouds and circumstellar envelopes, including the important role that polycyclic aromatic hydrocarbons might play in this, it was the detection in 2006 of rotational line emission from C6H- that galvanized a systematic study of the abundance, distribution, and chemistry of anions in the interstellar medium. In 2007, the Cassini mission reported the unexpected detection of anions with mass-to-charge ratios of up to ∼10 000 in the upper atmosphere of Titan; this observation likewise instigated the study of fundamental chemical processes involving negative ions among planetary scientists. In this article, we review the observations of anions in interstellar clouds, circumstellar envelopes, Titan, and cometary comae. We then discuss a number of processes by which anions can be created and destroyed in these environments. The derivation of accurate rate coefficients for these processes is an essential input for the chemical kinetic modeling that is necessary to fully extract physics from the observational data. We discuss such models, along with their successes and failings, and finish with an outlook on the future.

Electrochemical Measurement of Dopamine Release and Uptake in Zebrafish Following Treatment with Carboplatin.

Post-chemotherapy cognitive impairment, also known as 'chemobrain,' is a neurological condition in which cognitive function is impaired as a result of cancer chemotherapy treatment. In this work, we used fast-scan cyclic voltammetry (FSCV) to measure electrically evoked dopamine release and uptake in whole brain preparations from zebrafish that have been treated with carboplatin, an agent associated with chemobrain. We administered carboplatin by addition to the fish's tank water or their food. One week of treatment with 100 µM carboplatin in the water was needed to significantly impair dopamine release (∼40 % of control); however, only one day of treatment through the zebrafish's food was needed to cause a similar impairment. Atomic absorption spectroscopy measurements suggested that administration through food resulted in higher initial levels of carboplatin compared to water administration, but water administration resulted in an increase over time. Uptake, determined by modeling stimulated release plots, was unaffected. These results are consistent with our previous findings of diminished neurotransmitter release in rats and support a role for zebrafish in chemobrain-related studies.

Application of crystallization-induced asymmetric transformation to a general, scalable method for the resolution of 2,8-disubstituted Tröger's base derivatives.

A general method for the gram scale resolution of 2-substituted and 2,8-disubstituted Tröger's base (TB) derivatives in 63-91% yield has been achieved through the application of crystallization-induced asymmetric transformation (CIAT). Enantiomeric ratios of the resolved TB derivatives range from 99.1:0.9 to >99.5:0.5. Among the Tröger's base compounds resolved are four synthetically valuable bromo and iodo derivatives.

Molecular rearrangement reactions in the gas phase triggered by electron attachment.

Bond formation and rearrangement reactions in gas phase electron attachment were studied through dissociative electron attachment (DEA) to pentafluorotoluene (PFT), pentafluoroaniline (PFA) and pentafluorophenol (PFP) in the energy range 0-14 eV. In the case of PFA and PFP, the dominant processes involve formation of [M - HF](-) through the loss of neutral HF. This fragmentation channel is most efficient at low incident electron energy and for PFP it is accompanied by a substantial conformational change of the anionic fragment. At higher energy, HF loss is also observed as well as a number of other fragmentation processes. Thermochemical threshold energies have been computed for all the observed fragments and classical trajectories of the electron attachment process were calculated to elucidate the fragmentation mechanisms. For the dominant reaction channel leading to the loss of HF from PFP, the minimum energy path was calculated using the nudged elastic band method.

Predictors of the Rate of Illicit Fentanyl Metabolism in a Cohort of Pregnant Individuals.

INTRODUCTION: Illicit fentanyl use is growing in the United States, including among pregnant persons. Despite the prevalence of illicit fentanyl in the drug supply, the pharmacokinetics of fentanyl remains understudied, especially for pregnant individuals. The variability of fentanyl pharmacokinetics influences detection of fentanyl in urine samples, the results of which can have significant legal consequences. For pregnant and parenting individuals, these legal consequences may include termination of parental rights. METHODS: Through this medical-legal lens, we conducted a retrospective cohort analysis using the electronic medical records of women receiving integrated prenatal care and substance use disorder treatment. A total of 420 medical records were reviewed and 112 individuals who had a positive fentanyl immunoassay and met the selection criteria were included. Metabolic ratios (level of norfentanyl/level of fentanyl) were calculated for each study individual. A linear regression analysis was used to determine if the following physiologic factors were predictors of the rate of fentanyl metabolism: hepatic function, renal function, body mass index, medication dosage, gestational age, and maternal age. RESULTS: Results indicated that advanced maternal age predicted a slower conversion of fentanyl to norfentanyl, whereas increased gestational age predicted a faster conversion. CONCLUSIONS: Variations in fentanyl metabolism in pregnancy highlight the importance of clinician vigilance when interpreting fentanyl rests results, especially for individuals with advancing maternal age. In such cases, clinician caution and advocacy may prevent unwarranted and unjust removal of a child from maternal custody.

Dissociative electron attachment to C2F5 radicals.

Dissociative electron attachment to the reactive C(2)F(5) molecular radical has been investigated with two complimentary experimental methods; a single collision beam experiment and a new flowing afterglow Langmuir probe technique. The beam results show that F(-) is formed close to zero electron energy in dissociative electron attachment to C(2)F(5). The afterglow measurements also show that F(-) is formed in collisions between electrons and C(2)F(5) molecules with rate constants of 3.7 × 10(-9) cm(3) s(-1) to 4.7 × 10(-9) cm(3) s(-1) at temperatures of 300-600 K. The rate constant increases slowly with increasing temperature, but the rise observed is smaller than the experimental uncertainty of 35%.

False-positive Fentanyl Urine Detection after Initiation of Labetalol Treatment for Hypertension in Pregnancy: A Case Report.

BACKGROUND: Labetalol hydrochloride (LH) is a pharmacologic treatment for hypertensive disease (HD) in pregnancy. However, for pregnant persons with substance use disorders (SUDs), LH may interfere with urine drug testing. CASE SUMMARY: We present 3 pregnant or postpregnant persons with SUDs who experienced presumptive positive urine immunoassays for fentanyl while prescribed LH for perinatal HD. DISCUSSION: Labetalol hydrochloride treatment for HD in pregnancy can result in presumptive positive urine immunoassays for fentanyl. Unrecognized or misinterpreted, this phenomenon can lead to significant consequences for pregnant and postpartum persons with co-occurring substance use and hypertensive disorders. Clinicians caring for pregnant persons with SUDs must be aware of this phenomenon and its sequelae when ordering and interpreting urine immunoassays for fentanyl.

Transmission and trapping of cold electrons in water ice.

Experiments are reported which show that currents of low energy ("cold") electrons pass unattenuated through crystalline ice at 135 K for energies between zero and 650 meV, up to the maximum studied film thickness of 430 bilayers, indicating negligible apparent trapping. By contrast, both porous amorphous ice and compact crystalline ice at 40 K show efficient electron trapping. Ice at intermediate temperatures reveals metastable trapping that decays within a few hundred seconds at 110 K. Our results are the first to demonstrate full transmission of cold electrons in high temperature water ice and the phenomenon of temperature-dependent trapping.

Delayed Norfentanyl Clearance During Pregnancy.

BACKGROUND: We report a case of delayed norfentanyl clearance in a 33-year-old pregnant woman. Norfentanyl is the major metabolite of fentanyl. CASE: A multigravid woman with opioid use disorder presented at 7 weeks of gestation for treatment. Despite opioid abstinence, her urine was positive for norfentanyl on 10 distinct gas chromatography-mass spectrometry urine screens. The results demonstrated a steady decrease of norfentanyl over the course of 70 days after her last fentanyl usage, far exceeding expected rates of fentanyl clearance. CONCLUSION: This case highlights the importance of acknowledging pregnancy, genetic, or medication-induced changes to fentanyl pharmacokinetics when interpreting urine tests, especially given the potential sequelae of a false-positive urine test result.

Metastable dissociation of anions formed by electron attachment.

A comprehensive analysis of metastable dissociation of 2,4-dinitrotoluene (DNT) parent anions formed by attachment of electrons of controlled energy is presented. We characterize the energy dependence and kinetic energy release of the reaction which competes with autodetachment. A surprising finding is a highly exothermic metastable reaction triggered by the attachment of thermal electrons which we relate to the well-known electrostatic ignition hazards of DNT and other explosives. Quantum chemical calculations are performed for dinitrobenzene in order to elucidate the process of NO abstraction.

Ex Vivo Measurement of Electrically Evoked Dopamine Release in Zebrafish Whole Brain.

Zebrafish (Danio rerio) have recently emerged as useful model organism for the study of neuronal function. Here, fast-scan cyclic voltammetry (FSCV) at carbon-fiber microelectrodes was used to measure locally evoked dopamine release and uptake in zebrafish whole brain preparations and results were compared with those obtained from brain slices. Evoked dopamine release ([DA]max) was similar in whole brain and sagittal brain slice preparations (0.49 ± 0.13 µM in whole brain and 0.59 ± 0.28 µM in brain slices). Treatment with α-methyl-p-tyrosine methyl ester (αMPT), an inhibitor of tyrosine hydroxylase, diminished release and the electrochemical signal reappeared after subsequent drug washout. No observed change in stimulated release current occurred after treatment with desipramine or fluoxetine in the whole brain. Treatment with the uptake inhibitors, nomifensine or GBR 12909 increased [DA]max, while treatment with sulpiride, a D2 dopamine autoreceptor antagonist, resulted in increased stimulated dopamine release in whole brain, but had no effect on release in slices. Dopamine release in whole brains increased progressively up to an electrical stimulation frequency of 25 Hz, while release in slices increased up to a frequency of only 10 Hz and then plateaued, highlighting another key difference between these preparations. We observed a lag in peak dopamine release following stimulation, which we address using diffusion models and pharmacological treatments. Collectively, these results demonstrate the electrochemical determination of dopamine release in the whole, intact brain of a vertebrate species ex vivo and are an important step for carrying out further experiments in zebrafish.

Factors that influence producer decisions to implement management strategies.

Cow-calf enterprises in the USA are widely divergent in size, locale, resource availability, management skill, and market focus. Furthermore, variation exists in dependence on the cow-calf enterprise as a primary source of income, perception about the utility of a particular management practice or technology, and assessment of cost: benefit resulting from implementation impact decisions. Enterprises with larger cow inventories, greater dependence on income from the cattle enterprise, and that retain ownership further into the supply chain beyond the cow-calf operation are more likely to institute management protocols such as vaccination programs, defined calving seasons, and reproductive technologies. Successful cow-calf managers place the highest priority on herd nutrition, pasture and range management, herd health, financial management marketing, production management, and genetics. Management practices are more likely to be adopted when they align with a manager's perception of the utility, labor availability, favorable cost: benefit outcomes and profit motivation.

The evolution of lean beef: identifying lean beef in today's U.S. marketplace.

Changes in cattle breeding and management coupled with extensive trimming of visible fat from retail cuts have resulted in the wide-spread availability of lean beef to U.S. consumers. Despite these changes, there is limited awareness regarding the reduced total fat content and the favorable fatty acid profile of beef. Relative to the calories it contributes, the impact of beef on the nutritional quality of the American diet via its contribution of protein and certain key micronutrients is often under appreciated. The following discussion documents the progressive reduction in fat content of U.S. beef during the past 30 years, highlights ongoing efforts to update United States Department of Agriculture nutrient data for beef, and summarizes findings from randomized controlled trials of beef and plasma lipid outcomes. Beef is a popular, nutrient-dense food and the availability of at least 29 lean cuts of beef in the U.S. marketplace can help consumers meet their cardiovascular health goals.

Spectroscopy and metastability of CO2 2+ molecular ions.

The spectroscopy and metastability of the carbon dioxide doubly charged ion, the CO(2) (2+) dication, have been studied with photoionization experiments: time-of-flight photoelectron photoelectron coincidence (TOF-PEPECO), threshold photoelectrons coincidence (TPEsCO), and threshold photoelectrons and ion coincidence (TPEsCO ion coincidence) spectroscopies. Vibrational structure is observed in TOF-PEPECO and TPEsCO spectra of the ground and first two excited states. The vibrational structure is dominated by the symmetric stretch except in the TPEsCO spectrum of the ground state where an antisymmetric stretch progression is observed. All three vibrational frequencies are deduced for the ground state and symmetric stretch and bending frequencies are deduced for the first two excited states. Some vibrational structure of higher electronic states is also observed. The threshold for double ionization of carbon dioxide is reported as 37.340+/-0.010 eV. The fragmentation of energy selected CO(2) (2+) ions has been investigated with TPEsCO ion coincidence spectroscopy. A band of metastable states from approximately 38.7 to approximately 41 eV above the ground state of neutral CO(2) has been observed in the experimental time window of approximately 0.1-2.3 mus with a tendency towards shorter lifetimes at higher energies. It is proposed that the metastability is due to slow spin forbidden conversion from bound excited singlet states to unbound continuum states of the triplet ground state. Another result of this investigation is the observation of CO(+)+O(+) formation in indirect dissociative double photoionization below the threshold for formation of CO(2) (2+). The threshold for CO(+)+O(+) formation is found to be 35.56+/-0.10 eV or lower, which is more than 2 eV lower than previous measurements.